tooth agenesis

Etiology

 mutations in AXIN2 in familial tooth agenesis (15042511)

Physiopathology

The formation of teeth is one example of the intricate cooperation of different genetic pathways that lead to the morphogenesis of human facial features. Animal studies have shown that tooth development requires a sequential array of epithelial-mesenchymal interactions involving many signaling molecules like growth factors and their receptors, transcription factors and further modifier proteins. Interestingly, there is remarkable conservation of many of these pathways, as they are also employed in the shaping of other craniofacial structures.

Human tooth agenesis can present either as an isolated trait or as part of a syndrome. The isolated, non-syndromic form is quite common even if missing wisdom teeth are disregarded. Most often it affects just one or two upper lateral incisors or premolars. There are, however, many families or individuals with a history of severe tooth agenesis.

Interestingly, different patterns of missing teeth such as mostly posterior, more anterior, mostly incisor or totally mixed are also observed.

Genetic and molecular studies in mice have shown that the paired box protein Pax9 and the homeobox protein Msx1 are mesenchymally-expressed transcription factors which are selectively activated in the early tooth bud and are required for the maintenance of Bmp4 expression (bone morphogenetic protein 4).

Bmp4 is a signaling molecule required for the formation of an epithelial signaling center, the enamel knot and directs progression to the next stage of odontogenesis. Mice in which Pax9 and/or Msx1are completely missing show an arrest of tooth development at the bud stage.

Over the past decade, we and others have analyzed families with tooth agenesis for genetic variations in these genes and discovered that some of the families with a more anterior pattern of tooth agenesis had MSX1 mutations while others with a posterior pattern showed changes in the PAX9 gene.

The extension of our investigations to functional studies demonstrated that Pax9 but not Msx1 was able to activate both Bmp4 and Msx1 expression. However, the addition of Msx1 could amplify Pax9-mediated Bmp4 and Msx1 activation considerably.

In contrast, the Pax9 mutants that had been identified in the tooth agenesis families were not able to activate Bmp4 and Msx1 expression.

The mechanism of this loss of function is a deficit in binding of the Pax9 paired domain to the promoter DNA sequences of the two target genes(7).

A third gene, AXIN2, has been implicated in the mixed form of tooth agenesis after it was found by Lammi et al. that certain AXIN2 mutations cause tooth agenesis and predispose to colon cancer in one large family and in a sporadic case.

AXIN2 is a regulator in the Wnt signaling pathway, which is ubiquitously utilized throughout development and also includes the APC (adenomatous polyposis coli) gene product.

Although the AXIN2 gene is expressed in dental mesenchyme along with many other genes, it was not anticipated to be a “tooth agenesis” gene because of its more widespread expression. Only a family study with linkage analysis could reveal its importance for odontogenesis.

The fourth tooth agenesis gene turned out to be a gene which is well-known by geneticists for its role in the syndrome hypohidrotic ectodermal dysplasia (HED).

An isolated form of tooth agenesis was not expected to be associated with EDA mutations and we were quite surprised to find an EDA mutation in our largest tooth agenesis family.

Once EDA had been identified as a non-syndromic tooth agenesis gene, more and more families with X-linked isolated tooth agenesis were shown to have an EDA gene mutation.

It is predominantly responsible for incisor agenesis patterns. EDA belongs to the family of tumor necrosis factor-like proteins which are signaling molecules and as such, released from their cells of origin.

After binding to their specific target receptors on recipient cells, they activate the NFκB pathway, which consists of a complex assortment of intracellular proteins.

The EDA receptor EDAR and two of the intracellular accessory proteins called EDARADD and NEMO can also cause ectodermal dysplasia-like syndromes if mutated, though NEMO mutations are associated with the phenotypically distinct syndromes incontinentia pigmenti in females and ectodermal dysplasia with immunodeficiency in surviving males.

In collaboration with a Swiss research group we sought to determine the functional differences between EDA mutations that cause full-blown HED and those that are found in isolated tooth agenesis. We were able to show that the former lose all signaling capability while the latter retain residual function (manuscript in preparation). Thus we conclude that tooth development requires a higher dosage of EDA signaling than hair and gland development.

Four genes have been identified in 2010 as causing tooth agenesis. There are, however, many patients with hypodontia who do not have a mutation in any of these genes.

References

 Genetics and human malformations. Mues G, Kapadia H, Wang Y, D’Souza RN. J Craniofac Surg. 2009 Sep;20 Suppl 2:1652-4. PMID: 19816326 [Free]